Inhibition of vacuolar H plus ATPase enhances sensitivity to tamoxifen via up-regulation of CHOP in breast cancer cells
Woo Chul Noh ; Young-Sun Kim ; Hyun-Ah Kim ; Yun-Han Lee ; Hyeon-Ok Jin ; Eun-Kyu Kim ; Chang-Sun Hwang ; Jong-Il Kim ; Yoon Hwan Chang ; Seok-Il Hong ; Young-Jun Hong ; In-Chul Park ; Jin Kyung Lee
Biochemical and Biophysical Research Communications, Vol.437(3) : 463~468, 2013
Biochemical and Biophysical Research Communications
Resistance of estrogen receptor-positive breast cancer cells to tamoxifen represents a major barrier to the successful treatment of breast cancer. In the present study, we found that vacuolar H+ ATPase (vATPase) inhibitors, bafilomycin A1 and concanamycin A, sensitize tamoxifen-induced cell death. siRNA targeting ATP6V0C, a 16-kDa hydrophobic proteolipid subunit of vATPase that plays a central role in H+ transport, markedly increased cell death induced by tamoxifen. Interestingly, bafilomycin A1 induced up-regulation of DR4/DR5 and CHOP. Knock-down of CHOP by siRNA suppressed the cell death induced by bafilomycin A1 and tamoxifen, suggesting that bafilomycin A1-mediated CHOP activation sensitizes to tamoxifen. In addition, we found that bafilomycin A1 enhances TRAIL-induced cell death in breast cancer cells. Furthermore, we showed that combination of vATPase inhibitors with tamoxifen also effectively induced cell death in HER2- and ERα-overexpressing breast cancer cells. Overall, our results demonstrate that inhibition of vATPase can potentiate the apoptotic effects of tamoxifen through up-regulation of CHOP.